Amnestic syndromes and age-associated cognitive decline present significant morbidity, yet have few effective treatments. The long-term goals of this proposal are to characterize the neurobiological substrates of cognitive decline associated with aging and to develop therapeutic strategies to treat such decline. These goals dovetail with the NIH mission to support innovative research, extend healthy life and reduce the burdens of illness and disability The project will study fundamental mechanisms of brain rhythm interactions relevant to episodic memory coding using a rat model of amnesia and cognitive aging. The specific aims will test a novel strategy to improve memory performance, and evaluate potential episodic memory encoding mechanisms. In normal rats, memory performance is impaired by disrupting medial septal function, and conversely, improved by electrical stimulation of the septum. By simultaneously recording hippocampal EEG, stimulating the fornix, and tracking behavior in a Radial Arm Water Maze (RAWM), we will directly evaluate the physiological and behavioral consequences of different patterns of electrical stimulation. The specific aims are to ameliorate memory in rats made amnestic by medial septal inactivation, and to improve memory in aged rats who have naturally occurring spatial deficits. We will test the hypothesis that coherent activity between theta (4-10 Hz) and gamma (30-50 Hz) frequencies are crucial for memory encoding or retrieval. We predict that theta-gamma coherence will predict memory performance, and that stimulation patterns that increase such coherence will concomitantly enhance memory mechanisms. The results of the proposed experiments will elucidate the influence of endogenous synchronous rhythmicity in memory, and may lead to therapeutic interventions for improving memory in people. Cognitive decline and memory impairments often occur during old age, despite the absence of Alzheimer's disease or other illness. This project tests an approach to repair learning deficits in both young rats with amnesia and old rats with natural memory impairments using electrical stimulation in the brain. As the population of the US aged 65 and over increases over the next decade, such treatments will become a more urgent need in our aging society.